The renin-angiotensin system (RAS) or renin-angiotensin-aldosterone system (RAAS) is a hormonal system that regulates blood pressure and fluid balance. Blocking the RAS can reduce blood pressure. As such, clinical interventions blocking RAS, including inhibitors of angiotensin-converting enzyme (ACE) and angiotensin receptor blockers (ARBs), have been developed to treat hypertension.
Typically, the prohormone angiotensinogen is converted to the inactive precursor Angiotensin I, which is then converted by ACE to the active peptide hormone Angiotensin II (Ang II). Ang II can be further metabolized to Ang III, Ang IV, and Ang(1-7).
In humans, Ang II effects are mediated through seven-transmembrane G-protein coupled receptors, including angiotensin-1-receptor (AT1R) and angiotensin-2-receptor (AT2R). The blood pressure effects of Ang II are primarily mediated by AT1R. Activation of the AT1R can lead to various effects, including vasoconstriction leading to increased blood pressure. Conversely, blocking the AT1R can reduce blood pressure. Several angiotensin receptor blockers have been developed to treat hypertension.
One of the first angiotensin receptor blockers (ARBs) developed was the peptidic AT1R antagonist saralasin (i.e., [Sar1, Val5, Ala8]AngII) in the 1970's, which was approved by the FDA and sold as SARENIN in the US. Another peptidic antagonist, sarilesin (i.e., [Sar1, Ile8]AngII) entered clinical trials in Japan.
Clinical utility of both these compounds was limited by several factors, including partial agonist activity, short duration of action, and administration by continuous intravenous infusion. Subsequently, research and development activities in this area turned to the sartan class of non-peptidic small molecule ARBs, such as losartan, valsartan, and others, which did not have partial agonist activity and could be given orally. Several non-peptidic ARBs have been approved for therapeutic use, and SARENIN was withdrawn from the market.
The sartan class of non-peptidic small molecule ARBs are not recommended for use during pregnancy. Fetal exposure to ARBs can lead to neonatal and long-term complications. For example, it has been recommended that maternal treatment with the sartans be avoided in second and third trimesters of pregnancy. Thus, there is a lack of treatment options for hypertension disorders during pregnancy.